anales de psicología, 2013, vol. 29, nº 1 (enero), 293-300
Murcia (España)
http://dx.doi.org/10.6018/analesps.29.1.138231
Frontal variant of Alzheimer's disease and typical Alzheimer's disease:
A comparative study
Bernardino Fernández-Calvo1*, Francisco Ramos2 Virginia Menezes de Lucena3
1 Department of Psychology. CCHLA. Federal University of Paraiba, Brazil
2 Department of Personality, Assessment and Psychological Treatments. University of Salamanca, Spain
3 Department of Internal Medicine. CCM. Federal University of Paraiba, Brazil
Título: La variante frontal de la enfermedad de Alzheimer y la enfermedad
de Alzheimer típica: un estudio comparativo.
Resumen: Una de las características de la Enfermedad de Alzheimer (EA)
es su heterogeneidad clínica. Así, la presentación atípica frontal o disejecu-
tiva es cada vez más conocida, aunque los factores subyacentes se descono-
cen. En este estudio se comparó el rendimiento neuropsicológico de dos
grupos de pacientes con EA (variante frontal -EAvf- y típica -EAT-). El
grupo EAvf (n = 13) fue seleccionado por la existencia de una hipocapta-
ción frontal. Los resultados revelaron que el grupo EAvf manifestó un tras-
torno disejecutivo grave, una sintomatología neuropsiquiátrica más severa
(desinhibición y apatía), mayor deterioro funcional y generó mayor sobre-
carga en el cuidador que el grupo EAT sin afectación frontal (n = 47). A
pesar de que el grupo EAvf rindió más bajo en todos los test neuropsicoló-
gicos, solo se encontraron diferencias significativas entre ambos grupos en
las tareas de velocidad de procesamiento y visuoconstrucción. El análisis de
regresión logística reveló que las puntuaciones de velocidad de procesa-
miento y flexibilidad mental predicen significativamente el diagnostico de
EAvf. La existencia de reflejo de graspin, anosognosia y la no posesión del
APOE e4 también fue más prevalente en el grupo EAvf. Este grupo
mostró una predominancia de varones y fue más propenso a tener una his-
toria familiar positiva para la EA. Para concluir, el estudio sugiere que la
EAvf representa un subtipo de EA que parece tener características clínicas,
neuropsicológicas y genéticas diferentes a la EAT.
Palabras clave: Variante frontal de la enfermedad de Alzheimer; funciones
ejecutivas; anosognosia; Apolipoprotein E; déficits neuropsicológicos; tras-
tornos neuropsiquiátricos.
Introduction
The typical presentation of Alzheimer's disease (AD) implies
a deterioration of episodic memory, with less severe deficits
in attention, semantic memory, and visuospatial skills (Perri,
Watson & Hodges, 2000), which is related to initial
neuropathological lesions in the medial temporal lobe
(entorhinal cortex and hippocampal formation), subsequent-
ly extending to other regions associated with the neocortex
(Braak & Braak, 1991).
However, some authors suggest that impairment of the
executive functions (EF) (Lafleche & Albert, 1995) and the
neuropsychiatric alterations (Mega, Lee, Dinov, Mishkin,
Toga & Cummings, 2000) can also be early characteristics of
AD, with high prognostic value (Chen, Sultzer, Hinkin,
Mahler & Cummings, 1998; Palmer et al., 2011). In this con-
text, other profiles of cognitive impairment (Grady et al.,
1988; Stopford, Snowden, Thompson & Neary, 2008), with
a different evolution (Galton, Patterson, Xuereb & Hodges,
2000; Lambon, Patterson, Graham, Dawson & Hodges,
2003) have been described.
* Dirección para correspondencia [Correspondence address]:
Dr. Bernardino Fernández Calvo. Departamento de Psicologia. Univer-
sidade Federal da Paraíba, Cidade Universitária. Castelo Branco. João
Pessoa, 58059-900, PB Brasil. E-mail: bfcalvo@usal.es
© Copyright 2013: Servicio de Publicaciones de la Universidad de Murcia.
ISSN edición impresa: 0212-9728. ISSN edición web (http://revistas.um.es/analesps): 1695-2294
Abstract: Clinical heterogeneity is one of the characteristics of Alzheimer's
disease (AD). Hence, the atypical frontal or dysexecutive presentation is
becoming increasingly well-known, although the underlying factors are still
unknown. In this study, the neuropsychological performance of two
groups of patients with AD (frontal variant--ADfv--and typical--TAD)
were compared. The ADfv group (n = 13) was selected due to the exist-
ence of frontal hypoperfusion on a simple photon emission computer to-
mography (SPECT). The results revealed that the ADfv group displayed a
severe dysexecutive disorder, more severe neuropsychiatric symptomatolo-
gy (disinhibition and apathy), more functional impairment, and it generated
a higher caregiver overload than the TAD group without frontal impair-
ment (n = 47). Despite the facts that the ADfv group’s performance was
poorer in all the neuropsychological tests, significant group differences
were only found in the processing speed and visuoconstruction tasks. Lo-
gistic regression analysis revealed that the processing speed and mental
flexibility scores significantly predicted a diagnosis of ADfv. The existence
of the grasp reflex, anosognosia, and the absence of apolipoprotein E epsi-
lon 4 allele (APOE e4) were also more prevalent in the ADfv group. This
group had a predominance of males and it was more likely to have a posi-
tive family history of AD. To conclude, the study suggests that ADfv rep-
resents a subtype of AD that seems to have different clinical, neuropsycho-
logical, and genetic characteristics from TAD.
Key words: Frontal variant Alzheimer’s disease; executive functions;
anosognosia; Apolipoprotein E; neuropsychological deficits; neuropsychi-
atric disorders.
This heterogeneity of AD was revealed in the results of a
series of neuropathological (Galton et al., 2000; Kanne,
Balota, Storandt, McKeel & Morris, 1998), neuropsychologi-
cal (Becker, Huff, Nebes, Holland & Boller, 1988; Stopford
et al., 2008), and neuroimaging (Grady et al., 1990) studies
that established the existence of three subtypes or atypical
presentations of AD: visual agnosic, aphasic and apraxic
(Wallin & Blennow, 1996). These subtypes are closely relat-
ed to the location, degree, and type of neuropathology pre-
sent in each one (Galton et al., 2000; Kanne et al., 1998;
Lambon et al., 2003).
In the last decade, another subtype of AD has been dif-
ferentiated and referenced. Some neuroimaging studies con-
firm the presence of a subgroup of patients with early AD
who display frontal and temporal-parietal hypometabolism
with neuropsychiatric (Chase, Burrows & Mohr, 1987;
Grady et al., 1990; Perani et al., 1988) and dysexecutive dis-
orders (Mann, Mohr, Gearing & Chase, 1992). Johnson,
Head, Kim, Starr & Cotman (1999) detected a subtype of
patients, which they called a frontal variant of AD (ADfv),
which correlates neuropathologically with a higher number
of neurofibrillary tangles (NTFs) in the frontal lobe, and ex-
cessive dysexecutive deficit (e.g., Trail Making Test-A
[TMT-A] and FAS verbal fluency test [FAS]) in comparison
to other patients with typical AD (TAD). Subsequently, this
executive subgroup of AD has also been reported in a series
- 293 -
294 Bernardino Fernández-Calvo et al.
of clinical cases (Jeong, 2003; Larner, 2006), clinical-
anatomo-pathological descriptions (Alladi et al., 2007;
Habek, Hajnsek, Zarkovic, Chudy & Mubrin, 2010; Taylor,
Probst, Miserez, Monsch & Tolnay, 2008), and neuropsy-
chological studies (Back-Madruga et al., 2002; Binetti, Magni,
Padovani, Cappa, Bianchetti & Trabucchi, 1996; Woodward
et al., 2010a).
With regard to patients with TAD, neuropsychological
findings show that people affected with ADfv are slower to
process information (Back-Madruga et al., 2002), their func-
tional performance is poorer (Back-Madruga et al., 2002;
Swanberg, Tractenberg, Mohs, Thal & Cummings, 2004;
Woodward et al., 2010a), their global impairment progresses
faster (Woodward et al., 2010a), and they generate more
caregiver overload (Back-Madruga et al., 2002). It is im-
portant to note that these signs do not correlate with the se-
verity of the dementia. Moreover, these patients do not usu-
ally present positive family history of dementia, and their
symptoms are clinically (Woodward et al., 2010b), but not
neuropsychologically, more similar (Woodward et al., 2010a)
to frontotemporal dementia (FTD).
However, the neuropsychological identification of this
ADfv group has not yet been confirmed by means of neu-
roimaging tests, so these clinical-neuropsychological results
should be taken with precaution. Therefore, some of these
neuropsychological findings may not coincide with the neu-
ropsychological data contributed by publications of clinical-
neuropathological descriptions of patients with ADfv
(Habek et al., 2010; Taylor et al., 2008). In this sense, more
research is needed of people affected with ADfv, defined
through neuroimaging studies that confirm the
neuroanatomic connection of the executive deficits, in order
to analyze these and other neuropsychological characteris-
tics, or features of another nature (e.g., genetic--the presence
of apolipoprotein E epsilon 4 allele (APOE e4). A better de-
scription of ADfv could help to differentiate it from TAD
and FTD. In this sense, some authors note that certain pa-
tients affected with neuropathologically confirmed AD, and
who present executive deficits and neuropsychiatric disor-
ders in addition to amnesia, are diagnosed with FTD (Alladi
et al., 2007; Brun, 1987) or AD (Balasa et al., 2011) at the
onset of the clinical picture; a diagnosis that is maintained
until their deaths despite their manifesting, in the case of
FTD, clear mnestic disorders a few years after the diagnosis
(Alladi et al., 2007). Whereas other works suggest that, in the
atypical presentations of AD, there is a low prevalence of
APOE e4 allele (Snowden et al., 2007) and that AD patients
who are not APOE 4 carriers present greater executive def-
icits (Wolk et al., 2010).
Thus, this investigation attempts to compare the neuro-
psychological performance of the ADfv group, defined on
the basis of frontal hypoperfusion, and the TAD group
(without frontal hypoperfusion), also analyzing the relation
between these two groups of patients with the APOE e4 al-
lele. First, we hypothesize that the ADfv group will display
more executive deficits than the TAD group. Second, we
anales de psicología, 2013, vol. 29, nº 1 (enero)
hypothesize that both groups of participants will achieve a
similar neuropsychological performance in other non-
executive tests. However, we expect to find group differ-
ences in the frequency of the APOE e4 allele. Specifically,
the ADfv group will present a lower frequency of the APOE
e4 allele.
Method
Participants
The 84 participants in the study, 60 patients and 24 cog-
nitively healthy participants (CH), were selected from the
Neurology Section of the University Hospital of Salamanca
and from the family caregivers association of patients with
Alzheimer’s disease (AFA) of Salamanca, respectively. The
data of the patients were collected consecutively from July
to December 2002. In contrast, the data of the CH group
were collected from January to April of 2003. The CHs and
the person in charge of each patient gave their informed
consent to participate in the study.
The patients underwent a general clinical, neurological,
and neuropsychiatric examination, as well as the following
complementary studies: hemogram, Homocysteine, general
biochemistry,T4-TSH, vitamin B12 and folic acid, luetic se-
rology, APOE, a neuroimaging study: computed tomogra-
phy (CT) or magnetic resonance imaging (MRI) and simple
photon emission computer tomography (SPECT), using the
radiopharmaceutic 99mTc-hexamethylpropyleneamine
oxime (Tc99m-HMPAO). The assessment of each brain
SPECT was carried out visually by a radiologist who was
blind to the patients' clinical diagnosis, and who classified
the perfusion deficits according to the criteria proposed by
Holman et al. (Holman, Johnson, Gerada, Carvalho & Satlin,
1992).
The diagnosis of AD was made according to the criteria
of the National Institute of Neurologic, Communicative
Disorders and Stroke - Alzheimer's Disease and Related
Disorders Association (McKhann, Drachman, Folstein,
Katzman, Price & Stadlan, 1984). The diagnosis was sup-
ported by a neuropsychological assessment using screening
tests and a neuropsychological battery developed to assess
diverse cognitive functions (memory, language, praxis,
visuospatial function, attention, and executive functions),
which has been shown to be efficacious to diagnose demen-
tia (Contador, Fernandez-Calvo, Cacho, Ramos & Hernán-
dez-Martín, 2009). Only patients who met the criteria of
"probable" Alzheimer-type dementia and who had a mild
degree of dementia (CDR-1) according to the Clinical De-
mentia Rating (Hughes, Berg, Danziger, Coben & Martin,
1982) were included. All the patients were exempt from
signs of focal deficit in the neurological exploration--less
than four points on the Hachinski scale (Hachinski, et al.,
1975)--and from focal lesions in the CT or the MRI of the
brain. None of them met the criteria for major depression
according to the Diagnostic and Statistical Manual of Mental
 Frontal variant of Alzheimer’s disease and typical Alzheimer’s disease: A comparative study
Disorders, 4th edition (American Psychiatric Association,
1994).
The patients with AD were classified according to the
result of the brain SPECT as: frontal variant AD (ADfv, n =
13) or typical AD (TAD, n = 47). The pattern of
hypoperfusion found in the patients was: normal (3), frontal
(13), unilateral temporal (14), and bilateral temporoparietal
(30).
Lastly, during the clinical interview, we confirmed the
level of awareness of their own cognitive deficits, using a
semi-quantitative scale developed by Reed, Jagust & Coulter
(1993), the presence of positive family history of AD, de-
fined as having at least one biological parent with AD, ex-
trapyramidal signs (rigidity, tremor, bradykinesia), and grasp
reflex. In order to guarantee the diagnosis, each patient with
AD was followed up for at least five years to confirm the
AD diagnosis.
Control participants. The 24 CH participants were healthy
older Spanish-speaking people, who lived independently,
were not institutionalized, and who maintained their daily
activities, both basic and instrumental, integrally. People
who presented a history of psychiatric or neurological dis-
ease, or alcoholism, or who were under psychopharmacolog-
ical treatment and who had a score equal to or higher than
27 in the Mini Mental State Examination (MMSE] were ex-
cluded from the sample (Folstein, Folstein & McHugh,
1975). All the participants from the CH group performed
the same psychometric and neuropsychological tests and in
the same sequence as the group of patients.
Measures
All the participants were assessed by means of a broad
neuropsychological battery that explored diverse cognitive
functions, neuropsychiatric symptoms, and functional capac-
ity: Processing speed: Trail Making Test-part A (TMT-A;
Strauss, Sherman & Spreen, 2006); Digit Symbol Substitu-
tion subtests (DSST) of the Wechsler Adult Intelligence
Scale-revised (WAIS-R; Wechsler, 1981); Attention: Forward
digit span subtests (FDS) of the WAIS-R (Wechsler, 1981);
A-Random Letter Test of Auditory Vigilance (A-Test; Strub
& Black, 2000); Working memory: Backward digit span sub-
tests (BDS) of the WAIS-R (Wechsler, 1981); Verbal memory:
Hopkins Verbal Learning Test-RA (HVLT-RA; Benedict,
Schretlen, Groninger & Brandt, 1998); Visual memory: Ben-
ton Visual Retention Test (BVRT; Benton, 1981); Rey-
Osterreith Complex Figure (ROCF), delayed reproduction
(Rey, 1987); Semantic memory: animal fluency test (AF; Strauss,
et al., 2006); Visuoconstruction: Clock drawing test copy condi-
tion (CDT-C; Cacho et al., 2005); copy of the ROCF (Rey,
1987); Executive functioning: TMT-B (Strauss, et al., 2006),
Stroop test (part C) (Strauss et al., 2006), FAS (Strauss et al.,
2006); Similarities subtest (S) and Comprehension subtest
(C) of the WAIS-R (Wechsler, 1981); Performance strategies
of the ROCF (Rey, 1987); Neuropsychiatric Alteration : Neuro-
psychiatric Inventory (NPI; Vilalta-Franch, Lozano, Her-
295
nández, Llinàs, López-Pousa & López, 1999); Functional Al-
terations: Interview for Deterioration in Daily Living Activi-
ties in Dementia (IDDD; Böhm, Peña-Casanova, Aguilar,
Hernández, Sol & Blesa, 1998); Caregiver burden: Zarit Burden
Interview (ZBI; Izal & Montorio, 1994).
Statistical analyses
The statistical analysis of the data was carried out with
the software of the Statistical Package for Social Sciences
(SPSS) version 17. The χ2 contingency test was used for di-
chotomous variables. Group differences in the continuous
variables were analyzed with nonparametric tests (the Mann-
Whitney U or the Kruskal-Wallis H), as the groups had a
small and unequal n. Subsequently, multiple comparisons
were examined with Dunn's test. Lastly, logistic regression
analysis was used to determine the scores of the neuropsy-
chological tests that were capable of predicting the presence
or absence of ADfv. The level of significance was p < .05.
Results
Table 1 shows the participants' sociodemographic and clini-
cal characteristics. In comparison to the TAD group, the
ADfv group was made up predominantly of males, was
more likely to have a positive family history of AD, display-
ing significantly higher frequency of anosognosia, grasp re-
flex, and a lower proportion of the APOE e4 allele. Like-
wise, the ADfv group presented a significant increase in
functional and neuropsychiatric impairment and generated
greater caregiver overload, despite the fact that both groups
of patients were balanced in their degree of impairment and
years of evolution of symptomatology (TAD, range 1 to 4.5
years; ADfv, range 1.5 to 4.0 years).
The executive functioning of the ADfv group was also
significantly lower in all five executive tests administered
(Table 2). In view of these differences, we decided to deter-
mine the number of patients of each group with significantly
deteriorated scores in the executive tests, which consisted of
displaying < 2SDs from the CH group's mean in each meas-
ure, after standardizing by age and schooling.
A greater number of patients from the ADfv group had
significantly worse scores in the TMT-B-, Stroop C, and
FAS measures. In two other executive measures, there were
also a higher number of ADfv patients who performed
worse than the patients from the TAD group, although the
difference was marginal. Moreover, 11 of these 13 patients
from the ADfv group presented significantly worse scores in
at least 4 out of the 5 executive tests administered. In con-
trast, none of the TAD patients obtained deteriorated scores
in more than two executive tests (Table 3). Additionally, the
ADfv group employed worse production strategies when
copying the ROCF than the TAD group (χ2 = 20.4, p
<.001).
anales de psicología, 2013, vol. 29, nº 1 (enero)
296 Bernardino Fernández-Calvo et al.

Table 1. Sociodemographic and clinical characteristics of the participants.

Patients CH
Statistic p value†
TAD (N = 47) ADfv (N = 13) N = 24
Age; years 75.9 (5.5) 72.8 (7.6) 72.8 (4.6) H (2) = 4.2 ns‡
Sex (M/F) 43/57 69/31 45/54 χ2 (2) = 2.9 ns
Education; years 8.7 (4.2) 9.2 (3.3) 9.6(3.7) H (2) = 0.1 ns
Evolution; years 3.05 (2.1) 2.4 (1.5) ______ U = 268.0 ns‡
FH; n (%) 19 (40%) 9 (69%) ______ χ2 (1) = 3.3 .002
AG; n (%) 21 (45%) 12 (92%) ______ χ2 (1) = 9.3 .02
APOE e 4; n (%) 25 (53%) 2 (15%) ______ χ2 (1) = 5.3 ns
Presence ESP; n (%) 9 (20%) 3 (23%) ______ χ2 (1) = 0.1 .001
Presence GR; n (%) 1 (2%) 8 (62%) ______ χ2 (1) = 28.1 a, b
MMSE 22.8 (1.2) 22.5 (2.1) 28.3 (1.3) H(2) = 46.8* a, b
CDT-CM 6.2 (1.8) 5.4 (2.1) 8.9 (1.1) H(2) = 31.0* a, b, c
NPI 10.8 (4.6) 19.9 (9.2) 0.7 (2.5) H(2) = 12.3* a, b, c
IDDD 45.2 (4.5) 55.6 (6.8) 33.3 (0.4) H(2) = 54.3* .04
ZBI 20.2 (10.0) 28.2 (12.3) _______ U = 195.0* ns‡
Note. TAD = traditional Alzheimer's disease; ADfv = Alzheimer's disease frontal variant; CH = healthy control subjects; FH = family history of AD; AG =
anosognosia; EPS = extrapyramidal signs; GR = grasp reflex; MMSE = Mini Mental State Examination; CDT-CM = clock drawing test command condition;
NPI = neuropsychiatric inventory; IDDD = interview for deterioration in daily living activities in dementia; ZBI = Zarit Burden Interview; The Standard de-
viation in brackets; χ2 = Chi square statistic; H Kruskal-Wallis statistic; U Mann-Whitney Statistic; a: CH and AD differences; b: CH and ADfv differences; c:
TAD and ADfv differences; *p < .001 between all the groups; † indicates the significance of p-value according to Dunn's test; ‡ indicates marginal difference.

Table 2. Comparison of means of the participants in the executive tests

Patients CH
H (2) Comparisons†
TAD (N =47) Adfv (N =13) (N = 24)
TMT-B; s 302.6 (152.4) 739.3 (429.0) 195.2 (72.2) 44.0* HC >TAD>ADfv
Stroop C; s 66.3 (45.9) 100.4 (40.3) 32.3 (6.6) 41.3* HC >TAD> ADfv
S 8.1 (3.7) 3.9 (1.8) 13.6 (4.2) 31.4* HC >TAD> ADfv
C 13.1 (3.9) 9.6 (5.4) 19.3 (3.5) 28.8* HC >TAD> ADfv
FAS 21.5 (11.3) 14.8 (16.1) 32.0 (13.1) 14.3* HC >TAD> ADfv
Note. TAD = traditional Alzheimer's disease; ADfv = Alzheimer's disease frontal variant; CH = healthy control subjects; TMT-B = Trail Making Test, part B;
S = Similarities of the WAIS-R; C = Comprehension of the WAIS-R; FAS = FAS verbal fluency test; The standard deviation is in brackets; s = seconds; H
Kruskal-Wallis statistic; *p < .001 among all the groups; † indicates the significance of p-value according to Dunn's test; ‡ indicates marginal difference.

Table 3. Frequency of deterioration in the executive tests

Executive scales TAD (N = 47) ADfv (N = 13)
χ2 p value
Patients below the cut-off point (%) Patients below the cut-off point (%)
TMT-B 18 (39%) 13 (100%) 7.9 .01
Stroop C 25(53%) 13 (100%) 8.9 .04
S 17 (36%) 11 (85%) 4.1 .05
C 8 (18%) 11 (85%) 2.3 .08
FAS 10(21%) 12 (92%) 11.4 .01
Note. TAD = traditional Alzheimer's disease; ADfv = Alzheimer's disease frontal variant; TMT-B = Trail Making Test, part B; S = Similarities of the WAIS-
R; C = Comprehension of the WAIS-R; FAS = FAS verbal fluency test.

The patients from the ADfv group displayed more apa- Table 4. Comparison of means of patients in the NPI subscales.
thy, disinhibition, and worse processing speed and NPI Subscale TAD (N = 47) ADfv (N = 17) p value
visuoconstruction than the TAD group (see Tables 4 and 5). Delusions 0.7 (0.9) 0.5 (0.9) .20
Hallucinations 0.1 (0.3) 0.2 (0.4) .60
It is important to note that the performance of the ADfv
Agitation 0.9 (0.9) 1.2 (1.5) .80
group was lower in all the cognitive functions analyzed. In Depression 0.8 (1.1) 1.4 (1.7) .33
fact, in some of them, we found marginal significance, such Anxiety 1.4 (1.7) 0.9 (1.1) .11
as the case of immediate and delayed visual memory. Euphoria 0.7 (1.2) 0.9 (1.1) .10
Apathy 1.9 (1.7) 5.8(3.0) .001
Logistic Regression Analysis Disinhibition 0.5 (0. 8) 3.9 (3. 8) .001
Irritability/Lability 1.0 (1.2) 1.5(2.2) .70
In the logistic regression analysis, we entered the scores Aberrant motor behaviors 1.1 (1.7) 1.9(2.2) .13
of the tests that were lower in the ADfv patients than in the Sleep disorders 0.9 (2.2) 1.1 (2.8) .45
Eating disorders 0.8 (1.7) 0.9 (0.9) .15
TAD patients (TMT-A, DSST, CDT-C, ROCF-DR, TMT- Note. NPI = neuropsychiatric inventory; TAD = traditional Alzheimer's dis-
B, Stroop- C, S, C, FAS). The model was significant (χ2 = ease; ADfv = Alzheimer's disease frontal variant; The standard deviation is
in brackets.

anales de psicología, 2013, vol. 29, nº 1 (enero)

 Frontal variant of Alzheimer’s disease and typical Alzheimer’s disease: A comparative study 297

13.3, p < .001); the TMT-B tests [Exp(B) = .97, CI: (.95–
.99), p = .02], FAS [Exp(B) = .78, CI: (.64–.94), p = .01], and
TMT-A [Exp(B) = .96, CI: (.95–.99), p = .01] significantly
predicted the presence of ADfv, correctly classifying 82% of
the patients (69% ADfv and 85% AD).
Discussion
This work reveals the existence of a subgroup of AD with
frontal hypoperfusion that differs from the rest of the pa-
tients with AD in a series of neuropsychological and genetic
characteristics. Moreover, we found that these differences
also include the clinical sphere. Our results show that
dysexecutive impairment is more pronounced and homoge-
neous in the ADfv subgroup than in the TAD group, to the
extent that approximately 77% of the participants of the
ADfv group displayed severe impairment in the five execu-
tive measures analyzed in the study. The other 13% showed
impairment in at least three executive tests. In contrast, 47%
of the patients of the TAD group scored within the normal
range in all the tests, whereas the rest of the patients showed
impairment in just one measure, and there was more hetero-
geneity in the deteriorated test.

Table 5. Participants' performance in the non-executive neuropsychological tests.

TAD (N = 47) ADfv (N = 13) CH (N = 24) H (2) Comparisons†
TMT-A; s 112.1 (70.4) 345.2 (84.6) 64.2 (26.3) 22.6* ADfv<TAD<HC
Processing speed
DSST 8.6 (4.9) 5.1 (6.9) 27.9 (8.2) 48.3* ADfv<TAD<HC
FDS 4.7 (0.8) 4.0 (1.5) 5.7 (1.0) 24.0* ADfv=TAD<HC
Attention
A-Test; n°e 3.4 (2.0) 4.0 (3.1) 0.7 (1.3) 12.4* ADfv=TAD<HC
Working memory BDS 3.5 (0.9) 3.0 (1.3) 4.9 (1.1) 13.7* ADfv=TAD<HC
VFR 11.2 (3.8) 8.4 (2.6) 22.8 (3.2) 39.9* ADfv=TAD<HC
VFR´ 0.6 (0.5) 0.4 (0.7) 8.3 (2.5) 62.7* ADfv=TAD <HC
Verbal memory VGR 2.9 (1.6) 1.8 (2.4) 8.9 (2.7) 38.9* ADfv=TAD <HC
VR 3.4 (2.0) 2.4 (1.5) 9.3 (2.1) 36.8* ADfv=TAD <HC
BVRT 6.6 (2.4) 5.0 (2.3) 9.8 (0.6) 36.0* ADfv=TAD <HC‡
Semantic memory AF 7.9 (2.7) 6.2 (3.7) 19.9 (4.2) 52.0* ADfv= TAD <HC
CDT-C 6.8 (1.8) 4.9 (2.0) 9.6 (0.6) 12.6* ADfv<TAD =HC
Visuoconstruction
ROCF-C 15.2 (10.2) 10.1 (7.6) 32.7 (3.1) 28.4* ADfv<TAD =HC
Note. TAD = traditional Alzheimer's disease; ADfv = Alzheimer's disease frontal variant; CH = healthy control subjects; TMT-A = Trail Making Test part A;
DSST = Digit Symbol Substitution subtest of the Wechsler Adult Intelligence Scale-revised (WAIS-R); FDS = Forward Digit Span subtest of the WAIS-R;
A-Test = A-Random Letter Test of Auditory Vigilance; BDS = Backward Digit Span subtest of the WAIS-R; VFR = verbal immediate free recall of the
Hopkins Verbal Learning Test-RA (HVLT-RA); VFR´ = verbal delayed free recall of the HVLT-RA; VGR = verbal Guided recall of the HVLT-RA; VR =
Verbal recognition of the HVLT-RA; BVRT = Benton visual retention test; ROCF-DR = Delayed reproduction of the Rey-Osterreith Complex Figure; AF=
animal fluency test; CDT-C = Clock drawing test copy condition; ROCF-C = Copy of the Rey-Osterreith Complex Figure; The standard deviation is in
brackets; s = seconds; nr e = total number of errors; * p < .001 among all the groups; † indicates the significance of p-value according to Dunn's test; ‡ indi-
cates marginal difference.

Therefore, we can consider that the existence of a
dysexecutive disorder (< 2 SD) at the onset of the disease
seems characteristic of a subgroup of patients with atypical
dysexecutive presentation of AD. Other neuropathological
and neuropsychological studies (Back-Madruga et al., 2002;
Stopford et al., 2008; Woodward et al., 2010a; Woodward et
al., 2010b) have observed this type of atypical presentation
with early impairment of the frontal lobe in AD. For exam-
ple, Stopford et al. (2008) found that 22% of the patients
studied presented impairment in a nonamnestic single do-
main (language, visuospatial and praxis), and the
dysexecutive presentation was the most frequent (9%). The
patients of this group were more prone to display frontal
hypoperfusion than the other patients. In contrast, patients
with aphasic presentation did not display frontal alterations
in the SPECT. Other neuroimaging studies (Grady et al.,
1988; Perani et al., 1988) also detected the presence of a
subgroup of AD with frontal hypoperfusion that coexists
with bilateral temporal and parietal dysfunction, but they did
not use a neuropsychological criterion to analyze the degree
of impairment of the executive deficits nor did they carry
out a comparative study with another type of patients with
TAD. To our knowledge, this investigation is the first work
that combined neuroimaging and a neuropsychological
method to define and analyze the ADfv group.
Furthermore, the ADfv group presents an increase in the
neuropsychiatric symptomatology, greater functional im-
pairment, and it generates greater caregiver overload than
the TAD group. On the one hand, these results confirm the
findings of other neuropsychological studies (Back-Madruga
et al., 2002; Woodward et al., 2010a), clinical (Larner, 2006;
Woodward et al., 2010b) and/or neuropathological (Habek
et al., 2010; Taylor et al., 2008); on the other hand, they
show the relation between dysexecutive disorder and the
presence of functional and behavioral impairments in early
AD (Chen et al., 1998), verifying that the increase in the
neuropsychiatric symptoms of AD (e.g., disinhibition) is sig-
nificantly related to greater impairment of the frontal lobe
(Bruen, McGeown, Shanks & Venneri, 2008; Mega et al.,
2000) and to caregiver overload (Mohamed, Rosenheck,
Lyketsos & Schneider, 2010). In this sense, caregivers of
other kinds of non-Alzheimer dementias show higher rates
of overload than caregivers of patients with AD (Ricci et al.,
2009).

anales de psicología, 2013, vol. 29, nº 1 (enero)

298 Bernardino Fernández-Calvo et al.
However, the performance of the ADfv group in other
neuropsychological skills is similar to that of the TAD
group, except for their greater impairment in processing
speed and visuoconstruction, with worse planning strategies.
This result partially coincides with that of Back-Madruga et
al. (2002) and corroborates the neuropsychological descrip-
tions carried out in the series of clinical cases with this vari-
ant of AD (Jeong et al., 2003; Johnson et al., 1999; Taylor et
al., 2008).
Lastly, our ADfv group presented a higher frequency of
grasp reflex and anosognosia, and lower presence of the
APOE e4 allele. The existence of anosognosia in the ADfv
group has also been described in the work of Taylor et al.
(2008). Moreover, Starkstein, Jorge, Mizrahi, Adrian & Rob-
inson (2007) suggest that the people affected by AD with
greater frontal impairment may develop anosognosia even at
initial stages of the disease, as our results indicate. Amanzio
et al. (2011) consider that the impairment in cognitive flexi-
bility may be a prerequisite for anosognosia in AD. In our
study, cognitive flexibility, measured with the TMT-B and
the FAS, is the executive component that undergoes the
greatest alteration in the ADfv group, and less in the TAD
group, and it significantly predicts, along with the TMT-A
score, the diagnosis in 69% of the cases of ADfv and it ex-
cluded the diagnosis in 85% of the cases of TAD.
However, we consider that the existence of greater apa-
thy and disinhibition in the ADfv group has to do with the
neuroanatomic relation (e.g., dorsolateral frontal and anteri-
or cingulate cortex) that seems to exist between these symp-
toms, executive functioning and anosognosia (Amanzio et
al., 2011; Starkstein, Brockman, Bruce & Petracca, 2010). In
this sense, the present results confirm the opinion of some
authors who state that flexible thinking and the ability to in-
hibit a response seem to be essential skills to become aware
of the cognitive deficits in the daily life of patients with AD
(Amanzio et al., 2011). Likewise, the most severe
visuoconstructive deficits of patients with focal brain dam-
age are related to anosognosia and the impairment of the
dorsolateral prefrontal cortex (Rinaldi, Piras & Pizzamiglio,
2010). In fact, Fink, et al. (1999) indicate that these struc-
tures are essential to monitor the congruence between one's
expectations and what is actually done when carrying out
goal-directed actions. It is feasible that an impairment of
these frontal structures, which generates incapacity to detect
the incoherence between a foreseen action and the action
performed when copying or reproducing models (Rinaldi et
al., 2010), may have caused more severe visuoconstructive
deficits in the ADfv group, compared to the TAD group.
Some authors relate the absence of the APOE e4 allele
in AD to a greater atrophy in the frontoparietal structures
(e.g., dorsofrontal-parietal atrophy; Wolk et al., 2010). Thus,
anales de psicología, 2013, vol. 29, nº 1 (enero)
the noncarriers of APOE e4 allele present greater impair-
ment of the executive functions (Wolk et al., 2010). In any
event, it is noted that other atypical presentations of AD
have also been associated with a low prevalence of APOE
e4, which suggests that this gene may not be very relevant as
a risk factor for atypical phenotypes (Snowden et al., 2007).
This study also has some limitations. First, the
dysexecutive disorder presented by the patients with AD
may be secondary to white matter hyperintensities in the
fronto-subcortical circuits. However, this seems improbable;
we included the criterion of scoring ≤ 4 on a Hachinski is-
chemic scale, which reduces the significant presence of vas-
cular disease. Second, it is possible that the participants of
the ADfv group presented frontotemporal dementia (FTD)
instead of AD, because of their notable neuropsychiatric and
dysexecutive disorder. Nevertheless, this seems improbable
for two reasons. On the one hand, the mean age at the onset
of the disease in the ADfv group was relatively higher (72
years) than the age generally observed in FTD (onset before
65 years). On the other hand, the ADfv group showed a
visuospatial deficit; a skill that is relatively well preserved in
the initial phase of frontotemporal dementia (Hutchinson &
Mathias, 2007). Lastly, there was no neuropathological con-
firmation of the clinical diagnoses presented in this study.
Conclusions
Despite these limitations, the results of the study show the
clinical heterogeneity of early AD by detecting a subgroup of
AD, called ADfv, with phenotypical clinical and neuropsy-
chological characteristics that are different from those of
TAD; characteristics that, in the absence of neuropa-
thological confirmation, seem to be associated with a variety
of risk factors and genes, and not merely with APOE. Alt-
hough ADfv is a rare atypical presentation (Wallin &
Blennow, 1996), it is necessary to carry out other studies in
order to advance in the phenotypical and neuropathological
description of this variant of AD. This information may help
to homogenize patients for pharmacological investigation
and facilitate clinical practice, improving the differential and
prognostic diagnosis among the diverse clinical phenotypes
of AD and other non-Alzheimer dementias (e.g., fronto-
temporal dementia).
Acknowledgements.- We thank all the participants for their time
and commitment to the study. The authors also thank Dr. Israel
Contador for his very helpful comments on this paper.
Funding support.- The study was supported in part by Velum
foundation.
 Frontal variant of Alzheimer’s disease and typical Alzheimer’s disease: A comparative study
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